Thursday, 21 September 2017

#ChariotMS & #ThinkHand: is it ever too late to treat MS?

It is never too early, nor too late, to treat MS. #Never2EarlyNor2Late #ChariotMS #ThinkHand

Summary: This post makes a case for a new treatment philosophy at Barts-MS based on the principle that “It’s never too early, nor too late, to treat MS”. The post also describes the influence of the London Underground, or tube, on our thinking about MS. This post is longer than usual and no summary can do it justice so please take the time to read it in full. Thank you.

What has the tube, or London Underground, have to do with MS? My rendition of London Underground map to explain the MS journey should come to mind. I was recently told that my published, earlier, version has achieved iconic status as it is frequently used by other people in their presentations. It is a pity because things have moved on since I created the published version. Firstly, it depicts MS as a one-way journey that starts in the at-risk period and terminates in death valley. Another negative is that it is an all or nothing picture; it is not layered, it is not subtle. You may have noticed that I often show the MS tube map with a cut onion; if you peel an onion too fast it is going to make you cry. My ultimate aim is to produce a fold-out MS tube map that will allow you to unfold the journey one segment at a time. In this way, you can look at one part of the MS journey at a time. Secondly, my latest version of the map has become very dense with many additional lines and one line that is still under construction. This under construction line, or the dotted grey line, is the one that leads to long-term remission, a cure and normal ageing. It is under construction because the data is yet to emerge showing we can cure MS. I added this line to give people with MS hope and to make the point that the journey is not necessarily a one-way journey. Other add-ons to the map that I am particularly proud of include the co-morbidity, lifestyle and wellness lines. These illustrate the importance of managing MS holistically. Despite its limitations and criticisms, I maintain that the MS tube map creates a framework for laying out what MS is for people with the disease. Healthcare professionals can also use the map as a reference point to help them pigeonhole their knowledge and for explaining MS to their patients.

What about the criticisms? The cynics, and trolls, never miss an opportunity to take a punt at me and say that I created the MS tube map on behalf of Pharma to promote the prescribing of DMTs. The truth is that Pharma has never had a say in its content. The only reasons DMTs are a large part of the map is because there has been an explosion in the number of DMTs available to treat MS and with this, the complexity of treating MS has increased.

Please note the MS tube map will never be complete. It needs to evolve and improve. So if you have any ideas about improving it please drop me an email (bartmsblog@google.com).



The real reason for penning this post is that DrK and I had a discussion on the tube last night about MS (yes, DrK and I are typical Londoners - we commute to and from work on the underground). Our discussion revolved around the observation that we as a group at Barts-MS are pushing two messages that may seem incongruent. (1) To treat early to prevent damage from occurring in the first place, but also (2) to treat late as there is always some neurological function to preserve. This led us to come up with a new slogan:


“It’s never too early, nor too late, to treat MS!” 

or in eSpeak 

#Never2EarlyNor2Late

What do we mean by this? It is clear that people with active MS do better with early access to treatment compared to delayed access to treatment. Similarly, people with MS treated with highly-effective treatments early (rapid-escalation or flipping the pyramid) do better than those who are started on less effective treatments first and escalated if necessary to highly effective therapies later (slow stepwise approach). However, even the former approach may not be early enough. We know that a significant number of people presenting with clinically isolated syndromes (CIS) already have substantial damage. Therefore we really need to define early, as being even earlier, and try and identify people in the asymptomatic phase of the disease, or in the at-risk period of MS, and treat them to prevent them getting MS in the first place. I am also very keen that we expand the diagnostic criteria of MS to include RIS (radiologically isolated syndrome) as part of the treatable MS spectrum. Approximately, 25% of RIS patients already have significant cognitive impairment. Why would we not want to treat these patients and prevent further damage?

It is never too late. At the moment all the trials that have led to licensed DMTs have excluded patients who are wheelchair users. The consequences of this are that many international guidelines, including NHS England guidelines, require us to stop DMTs once a patient reaches EDSS 7.0. We know this is wrong. We have emerging evidence that treatments still work in more advanced MS and slow down the progression of the disease in neuronal systems that still have reserve capacity, for example, the arms, speech and swallowing. Our #ThinkHand campaign’s main aim is to raise awareness about this issue and to get the MS community to take the preservation of upper limb function seriously. What we need is class 1 evidence (randomised-controlled trials) of the effect of DMTs on upper limb function in people with more advanced MS. This is why we are trying to get funding in place for our CHARIOT-MS study. The CHARIOT-MS study will tell us if subcutaneous cladribine, given to patients with more advanced MS (EDSS 6.0 to 8.0), will delay the inevitable loss of function of the upper limbs. Please note that Pharma has no interest in funding this trial; the liquid formulation of cladribine is generic and hence there is no financial incentive in place for them to do this trial. You may ask what about Mavenclad, the licensed oral formulation of cladribine? Unfortunately, the patent life on the oral formulation is too short; by the time a study in more advanced MS is done Mavenclad is likely to be generic.

In parallel to the CHARIOT-MS trial, we will continue to lobby Pharma. In my opinion, the four best agents, apart from Mavenclad, to test in more advanced MS are natalizumab, alemtuzumab, ocrelizumab and ofatumumab. Please note these are all high efficacy therapies. Insights that have led us to design the CHARIOT-MS study come from the ASCEND (natalizumab in SPMS) and ORATORIO (ocrelizumab in PPMS) trials. These studies indicate that we probably need a high efficacy therapy to make a difference in advanced MS. We are aware that Genzyme is developing a follow-on anti-CD52 monoclonal to replace alemtuzumab and Novartis have ofatumumab in phase 3 trials in RRMS. Therefore, which of the big guns, Genzyme, Biogen, Roche or Novartis are prepared to be bold and take-up the challenge of testing their drugs in more advanced MS? If anyone from one of these companies is reading this post can you please forward our message to the decision-makers in your companies?

Life tends to reward the bold, the risk-takers, and people who care. Which one of you cares enough about MS to take-up the challenge? The rewards of doing a study of this nature go way beyond economics. Can you imagine what the MS community will say about you as a company if you challenge the current dogma that ‘advanced MS is not modifiable’? One of the reasons for inviting so many company people as co-authors on our length-dependent axonopathy paper was to try and catalyse a change of thinking within your companies. We sincerely hope this is happening.

A softer and possibly easier option is to dig deep into your pockets and to make a large donation to DrK’s (@KlausSchmierer) CHARIOT-MS project. DrK is looking for a large donation to support his application to the NIHR for the CHARIOT study. He needs to bring the NIHR costs down to under £2.5M to have any chance of getting this trial funded.

DrK with a smile

Giovannoni et al. Is multiple sclerosis a length-dependent central axonopathy? The case for therapeutic lag and the asynchronous progressive MS hypotheses. Mult Scler Relat Disord. 2017 Feb;12:70-78.

Trials of anti-inflammatory therapies in non-relapsing progressive multiple sclerosis (MS) have been stubbornly negative except recently for an anti-CD20 therapy in primary progressive MS and a S1P modulator siponimod in secondary progressive MS. We argue that this might be because trials have been too short and have focused on assessing neuronal pathways, with insufficient reserve capacity, as the core component of the primary outcome. Delayed neuroaxonal degeneration primed by prior inflammation is not expected to respond to disease-modifying therapies targeting MS-specific mechanisms. However, anti-inflammatory therapies may modify these damaged pathways, but with a therapeutic lag that may take years to manifest. Based on these observations we propose that clinically apparent neurodegenerative components of progressive MS may occur in a length-dependent manner and asynchronously. If this hypothesis is confirmed it may have major implications for the future design of progressive MS trials.

CoI: multiple

26 comments:

  1. If Merck wont't do the study why don't you ask Merck to supply you with free Mavenclad and matching placebo? It will at least save you the drug costs and prevent trial subjects having to have repeat injections.

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    1. DrK needs to speak to Merck. I can't see any reason why they won't support this study.

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    2. Drug cost isn't a significant element on the costing sheet - you're laughing, but it's the truth. If Merck makes a significant donation to @BartsMS_Charity, say £1.5 million, that could make a real difference.

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    3. But what about the study subjects? Surely taking tablets is better than injections or infusions?

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    4. Sure we can survey that, but in the scheme of things this is minor (6-7 injections/year, for 2 years). There may also be safety advantage in using injections (personalized dosing according to individual lymphocyte count), which could be beneficial in older more disabled and generally more vulnerable pwMS.

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    5. The NIHR will not fund a study that potentially benefits a Pharma Company without them helping support the trial. If Merck simply gave free tablets and the NIHR picked-up the bill for the trial it would like the NIHR supporting a company trial. Merck would have to make it clear to the NIHR that this trial was not in their interests as oral cladribine would be off-patent and hence the trial results would only benefit follow-on generic cladribine tablets. Would an additional £1.5-2.0 Million contribution to the trial convince the NIHR otherwise? I suspect it may.

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  2. How much money do you need to support the study?

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    1. The project cost hovers just under £4.5 million. We need to raise roughly £3.5 million, I'd expect the NIHR to pay £1.5 million, the remaining £2 million need to come from MS Societies, charities, donors.

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    2. Merck will sending triple this at ECTRIMS. May be they could think twice about their marketing budget and kick-start your study.

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    3. One last point your budget seems too low. I suspect you need at least triple this budget to do this study.

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    4. You would be surprised at how low the NIHR can keep costs down when doing investigator-led trials.

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    5. Agree with ProfG. It's ridiculous for how little money investigator-led studies can be done. But money on the table there has to be. £2 million external, no more but also: no less.

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    6. Planned submission 28 Nov when pledges need to be in by. The project will last 5 years, study duration will be 2 years with 9HPT the primary outcome.

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    7. Dr K 7.21
      And the other £1m? Do you have that already? So £2m left to raise, £1.5m from NIHR ie 1 + 2 + 1.5 = 4.5

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  3. I know going on the tube is often hell, but this takes things to the extreme.

    One or four stops are missing, I'd venture.

    Where is the tube line for carers and family? I think that this is often overlooked.

    I think there also needs to be addressed the issue of continuity of care... with a a lifelong disease like this, surely patient-neurologist care is a relationship and not a one-off visit. Perhaps that should be given a nod: that patients rely on their neurologists to be there for them. I have spoken to a London neurologist recently who has 3,000 patients. She handed in her resignation last April and still the post remains unfilled. There might be 3,000 patients left standing. Or not...

    Then there is the disruption of politics and funding. NICE deserves a stop, surely: the gatekeepers and the pursekeepers.

    And then there is the totally random loop - the one of quacks and cures. HSCT, CCSVI, snake venom, hyperbaric chambers. That loop is greater than just 'alternative medicine' and is one filled with joy and despair and I think might even be haunted by the screams of those with dashed hopes. Surely the world of profiteers lurking at the edge of our sanity needs to be offered a season ticket?

    And finally, what about the internet? You name research, sure, but this blog is worth including, and others like it. It empowers and angers and offers a sense of engagement to a few. I'd say that for many people with MS the internet is the one thing that they can go to when a new symptom emerges or a new drug is offered. And the internet? Well - that's a whole tube map in itself.

    Sorry if I have suggested additions that are already there.

    Mind the (NHS funding) gap.

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    1. Very well written. You should help these bloggers improve their prose. I agree with everything you have said, but I wouldn't give CCSVI a dedicated stop. May you can decommission a line and have ghosts stations? Maybe you could call it the Tory line?

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    2. I agree. Very nicely penned. I will take all your suggestions into account when I next update the MS Tube Map. I like the idea of a ghost line as well; it could be used to bury a lot of things.

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  4. Aren't you being biased? I am not sure you can place cladribine in the same efficacy bracket as alemtuzumab, anti-CD20 and natalizumab. Surely you should be doing your study with one of the monoclonals?

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    1. Until we do head-2-head studies we will not know how effective cladribine is relative to the monoclonals. Based on the brain atrophy data it is probably not as effective as alemtuzumab or natalizumab (we are waiting for ocrelizumab atrophy data beyond year 2). However, cladribine is off patent and we, therefore, have access to a cheap generic formulation so why not go with cladribine? Cladribine also penetrates the CNS that may, or may not be, important in advanced MS.

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    2. Re: "Aren't you being biased?"

      Yes we are biased. We have made this clear in our disclosures, etc.

      Parenteral cladribine was one of the first drugs on our Barts-MS Essential Off-Label DMT list. We hope that the EMA licensing of Mavenclad will give our colleagues, in resource-poor medical environments, the confidence to start using generic cladribine to treat their patients with MS who can't afford licensed DMTs.

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  5. What does CHARIOT stand for? Who came up with the name?

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    1. It's one of mine: "Cladribine to halt deterioration in people with advanced MS" - CHARIOT MS

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    2. Well named; it fits your image as a white knight!

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  6. Is it not too late for all those people aged 50+ whose disease has 'burnt out'? They are left with no evidence of inflammation but severe disabilities and a damaged brain ill-equipped to face the ravages of ageing to come.

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  7. May I ask how much the MS Society UK is contributing?

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